Abstract Systemic lupus erythematosus (SLE) is chronic autoimmune disease with a strong genetic component of susceptibility. While polymorphisms in many genes can increase SLE risk, there is limited knowledge about the molecular mechanisms by which these variants contribute to SLE disease. Recent genome- wide association studies have identified variants of the ITGAM gene, encoding the CD11b chain of the CD11b/CD18 integrin, Mac-1, as major risk factors for SLE. A strong risk effect is mapped to rs1143679, a single-nucleotide polymorphism (SNP) resulting in an Arginine to Histidine substitution at position 77 (R77H). Studies in different cell types concluded that the R77H variant compromises ligand binding and various Mac-1 functions, without affecting integrin surface expression. How R77H affects ligand binding was not clear as it is located in the ?-propeller domain, outside the ligand-binding ?I- domain. Productive ligand binding requires that CD18 integrins undergo conformational (allosteric) changes that are relayed to the ?I ligand-binding domain. We uncovered that R77H has a defect in allostery relay that results in reduced binding affinity for complement C3. rs1143679 (R77H) is in strong linkage disequilibrium with rs1143678 (P1146S) and rs1143683 (A858V), located in the cytoplasmic and calf-1 regions of CD11b, respectively. While A858V is a conservative change not likely to alter Mac-1 function, the cytoplasmic SNP affects cell adhesion. The gaps in the field are the lack of information on how Mac-1 regulates functions relevant to SLE in specific cell types and the in vivo consequences of the ITGAM SNPs. This could be addressed in genetically engineered mice. However, the SNPs are in regions not conserved between mouse and human ITGAM. The goal of this proposal is to generate mice expressing a human/mouse CD11b chimera in a cell type specific manner in Mac-1 deficient mice, characterize these mice for Mac-1 expression and function and generate mice harboring R77H and P1146S in the human sequences of the chimera. We have generated the human/mouse chimera and shown efficient pairing with mouse CD18 and appropriate integrin function. We have placed the construct downstream of a LoxP-Stop cassette and shown Cre-induced expression in a cell line, which will allow cell type specific deletion when transgenic mice are mated to appropriate Cre driver mice. This is a high-risk proposal as there are potential pitfalls with generation of a chimeric integrin that recapitulates the phenotype of the human SNPs. The high reward is that modeling these SNPs in vivo will not only provide insights into how these SNPs modulate leukocyte functions in vivo and thus lupus susceptibility but may also aid in understanding the inhibitory function of Mac-1 in human SLE that could have relevance for non-carrier lupus patients and potentially result in new therapeutic leads.